Cell migration is central to many processes in the human body, such as the immune response, but can also be a component of chronic inflammation. The migration of mononuclear cells to the CNS is believed to be one factor underlying the pathogenesis of inflammatory diseases of the CNS.
One example is multiple sclerosis (MS) which is an autoimmune disease that affects the CNS, i.e. the brain and spinal cord. MS is characterized by weakness, tremors, and visual impairments. Other symptoms are slurred speech and impaired mobility, e.g. that the patients drag their feet, stumble, and frequently drop objects. These symptoms may remain mild, come and go, or become crippling—but they tend to get progressively worse with age (Hafler, 2004). MS usually affects women more than men. The disorder most commonly begins between ages 20 and 40, but can strike at any age. The exact cause is not known, but MS is believed to result from damage to the myelin sheath, the protective material which surrounds nerve cells. It is a progressive disease, meaning that the damage gets worse over time. Inflammation destroys the myelin, leaving multiple areas of scar tissue (sclerosis). The inflammation occurs when the body's own immune cells attack the nervous system.
One important step in the pathogenesis of MS is the migration of cells to the CNS, wherein self-reactive T-cells, and B-cells together with monocytes mediate inflammation of the CNS, thereby causing demyelination of axons. Chemokines and their receptors are proposed to play a major role in the recruitment of these leukocytes to CNS. Thus, a reduction of chemokine receptors may be an effective strategy to prevent migration of destructive cells to CNS. Important chemokine receptors described in MS pathology are CCR5 (a receptor for chemotactic proteins such as RANTES and MIP-1alpha), CXCR3 (a receptor for chemotactic proteins such as IP-10 and MIG), and CCR2 (a receptor for chemotactic proteins such as MCP1-3) (Trebst C et al., 2009).
Another step that can lead the lymphocytes to enter into the parenchyma of the CNS is adhesion of CD49d (very late antigen, VLA-4 expressed on T-cells and B-cells) to their receptors on endothelial cells, and thereby transmigrate through the blood-brain barrier. A reduction of CD49d can reduce the transmigration and accumulation of immune cells in the CNS (Steinman L, 2009).
In healthy individuals, immune cells cannot pass through the CNS capillaries and venules into the CNS tissue because the walls of the capillaries in the CNS are different from those in the rest of the body in that they have very closely packed cells which do not allow the passage of immune cells. This special feature of the CNS vascular system is referred to as the blood-brain barrier (BBB). Vascular endothelial growth factor (VEGF) has been described to induce breakdown of the BBB, which in turn can exacerbate the inflammatory response in autoimmune disease of the CNS (e.g. MS) (Proescholdt M A et al., 2002). A reduction of VEGF is an effective strategy to prevent the increased vascular permeability of BBB and thereby reduce the influx of destructive cells into CNS.
The inflammation causes nerve impulses to slow down or become blocked, leading to the symptoms of MS. Repeated episodes, or flare ups, of inflammation can occur along any area of the brain and spinal cord.
Symptoms vary because the location and extent of each attack varies. Usually episodes which last days, weeks, or even months, alternate with periods of reduced or no symptoms (remission). Recurrence (relapse) is common although non-stop progression without periods of remission may also occur.
Patients diagnosed as having MS can expect one of four clinical courses of disease, each of which might be mild, moderate, or severe:
1. Relapsing-Remitting
Characteristics: People with this type of MS experience clearly defined flare-ups (also called relapses, attacks, or exacerbations). These are episodes of acute worsening of neurological function. They are followed by periods of partial or complete recovery (remissions) free of disease progression.
Frequency: Most common form of MS at time of initial diagnosis. Approximately 85% of patients.
2. Primary-Progressive
Characteristics: People with this type of MS experience a slow but nearly continuous worsening of their disease from the onset, with no distinct relapses or remissions. However, there are variations in rates of progression over time, occasional plateaus, and temporary minor improvements.
Frequency: Relatively rare. Approximately 10% of patients.
3. Secondary-Progressive
Characteristics: People with this type of MS experience an initial period of relapsing-remitting MS, followed by a steadily worsening disease course with or without occasional flare-ups, minor recoveries (remissions), or plateaus.
Frequency: 50% of people with relapsing-remitting MS developed this form of the disease within 10 years of their initial diagnosis, before introduction of the “disease-modifying” drugs. Long-term data are not yet available to demonstrate if this is significantly delayed by treatment.
4. Progressive-Relapsing
Characteristics: People with this type of MS experience a steadily worsening disease from the onset but also have clear acute relapses (attacks or exacerbations), with or without recovery. In contrast to relapsing-remitting MS, the periods between relapses are characterized by continuing disease progression.
Frequency: Relatively rare. Approximately 5% of patients.
There is no consensus within the scientific community as to what triggers an attack. Patients with MS typically have a higher number of immune cells than a healthy person, which suggests that an immune response might play a role. The most common theories point to a virus or genetic defect, or a combination of both. There also appears to be a genetic link to the disease. MS is more likely to occur in northern Europe, the northern United States, southern Australia, and New Zealand than in other areas. Geographic studies indicate there may be an environmental factor involved. People with a family history of MS and those who live in a geographical area with a higher incidence rate for MS have a higher risk of the disease.
Medications such as interferon-beta, glatiramer acetate, and mitoxantrone can reduce the frequency and severity of attacks in people with relapsing-remitting MS and may reduce or delay future disability. Interferon-beta and mitoxantrone may also slow the progression of secondary progressive MS.
Treatment with interferon-beta or glatiramer acetate should begin as soon as relapsing-remitting MS has been diagnosed. Most specialists now agree that permanent damage to the nervous system may occur early on, even while the symptoms are still quite mild. Early treatment may help prevent or delay some of this damage.
Interferon beta treatment is however accompanied by several adverse effects. The most frequent adverse effects are flu-like symptoms: increased body temperature, feeling ill, fatigue, headache, muscle pain, convulsion, dizziness, hair thinning, and depression. Erythema, pain and hardness on the spot of injection are also frequently observed. Interferon therapy causes immunosuppression and can result in some infections manifesting in unusual ways.
Also corticosteroids may be given during a relapse to reduce inflammation and shorten the attack. The potent effect of corticosteroids can result in serious side effects which mimic Cushing's disease, a malfunction of the adrenal glands resulting in an overproduction of cortisol. The list of potential side effects is long and includes: increased appetite and weight gain; deposits of fat in chest, face, upper back, and stomach; water and salt retention leading to swelling and edema; high blood pressure; diabetes; black and blue marks; slowed healing of wounds; osteoporosis; cataracts; acne; muscle weakness; thinning of the skin; increased susceptibility to infection; stomach ulcers; increased sweating; mood swings; psychological problems such as depression; and adrenal suppression.
In 2004, the FDA approved the use of a monoclonal antibody (natalizumab, Tysabri®, Biogen Idec Inc., Cambridge, Mass., USA, and Elan Pharmaceuticals, Inc., Dublin, Ireland) for the treatment of patients with relapsing forms of MS (FDA News P04-107, Nov. 23, 2004).
While generally well tolerated, natalizumab is occasionally associated with severe adverse effects. Antibody therapy in general is costly, and there is a need for improvements inter alia with regards to efficacy.
Currently, a number of other monoclonal antibodies are being investigated for MS, including some that are already in use in other conditions. These include ocrelizumab (Genentech/Hoffmann-La Roche) daclizumab (Biogen Idec, Inc.), alemtuzumab (Campath®, MabCampath®, Bayer Schering, BTG, Genzyme, Millenium), and rituximab (Rituxan®, MabThera®, Genentech, Hoffmann-La Roche, Biogen Idec Inc.)
WO 2006/065751 concerns a CpG oligonucleotide prodrug that includes a thermolabile substituent on at least one nucleotide thereof. Therapeutic methods of using such thermolabile CpG oligonucleotide prodrugs are described. The induction of cytokines, in particular interferons, e.g. interferon-alpha, interferon-beta, or interferon-gamma is disclosed.
WO 2006/027776 concerns methods for regulating an AChE-associated biological pathway having a miRNA component, the methods comprising subjecting the AChE-associated biological pathway to an agent capable of regulating a function of the miRNA, thereby regulating the AChE-associated biological pathway. Said agents include modified polynucleotide sequences.
WO 2007/095316 relates generally to immunostimulatory nucleic acids, compositions thereof and methods of using the immunostimulatory nucleic acids. In particular the invention relates to palindrome-containing immunostimulatory nucleic acids and the use of these nucleic acids in treating disease.
WO 2004/016805 discloses a class of soft or semi-soft CpG immunostimulatory oligonucleotides that are useful for stimulating an immune response.
In summary, there is a need for improving existing therapies for MS, with the aim of improving efficacy, as well as reducing cost and adverse effects. There is also a need for developing new treatment strategies for the battle against MS.